Dendritic cells (DC) are antigen-presenting cells (APC) that initiate T cell-dependent immune responses (Steinman, 1991, Ann. Rev. Immunol. 9:271-296). In humans, plasmacytoid DC (pDC) are a DC subset characterized by their ultrastructural resemblance to Ig-secreting plasma cells (Grouard et al., 1997, J. Exp. Med. 185(6):1101-1111), their unique surface phenotype (CD4+IL-3R++CD45RA+HLA-DR+) (Grouard et al., 1997, J. Exp. Med. 185(6):1101-1111; Facchetti et al., 1999, Histopathology 35(1):88-9; Res et al., 1999, Blood 94 (8):2647-57), and their ability to produce high levels of IFNα in response to virus stimulation or to oligodeoxynucleotides (ODN) containing particular CpG motifs (Siegal et al., 1999, Science 284(5421):1835-7; Kadowaki et al., 2001, J Immunol 166(4):2291-5) and induce potent in vitro priming and Th-1 polarization of naive T cells following viral encounter (Cela et al., 2000, Nat Immunol 1(4):305-10; Kadowaki et al., 2000, J Exp Med 192 (2):219-26). pDC are believed to be derived from a precursor common with T cells and B cells (Grouard et al., 1997, J. Exp. Med. 185, 6:1101-1111; Res et al., 1999. Blood 94, 8:2647-57; Res et al., 1999, Blood 94 (8):2647-57; Bruno et al., 1997, J. Exp. Med. 185:875-884; Bendriss-Vermare et al., 2001, JCI 107 :835; Spits et al., 2000, J. Exp. Med. 192 (12):1775-84).
In the mouse, pDC have been recently identified by several groups as CD11clowB220hiGr1low cells, able to produce type I IFN in response to viral stimulation and exhibiting plasmacytoid morphology (Nakano et al., 2001, J. Exp Med, 194(8):1171-8 ; Paturel et al., 2001, Nat Immunol. 2(12):1144-1150; Bjorck, 2001, Blood 98(13):3520-6). Mouse pDC can also be obtained in large number in vitro, by differentiating bone marrow cells into dendritic cells in the presence of FLT3L.
In addition to their morphology, their IFNα production and their putative origin, pDC also differ from myeloid DC in their weak phagocytic activity (Grouard et al., 1997, J. Exp. Med. 185, 6:1101-1111), their weak IL-12 production capacity (Rissoan et al., 1999, Science 283:1183-1186), and the signals inducing their activation (Kadowaki et al., 2001, J. Immunol 166(4):2291-5). While recruitment of activated pDC should initiate immunity through naive T cell activation, immature or inactivated DC have been reported to induce immune tolerance, likely through induction of regulatory T cells (Jonuleit et al., 2001, Trends Immunol. 22:394; Bell et a., 2001, Trends Immunol 22:11, Roncarolo et al., 2001, JEM 193:F5; Jonuleit et al., 2000, JEM 162:1213). Moreover, pDC have been shown to induce IL-10 secreting T cells (Rissoan et a., 1999, Science 283:1183; Liu et al., 2001, Nature Immunol 2:585) and CD8 regulatory T cells (Gilliet et al., 2002, J. Exp Med. 195(6):695-704). Human natural IFN-producing cells (HuIPC) have also been shown to play an essential role in activating natural killer (NK) cells to kill virus-infected cells (Bandyopadhyay et al., 1986, J. Exp Med 164(1):180-95). Furthermore, pDC have been recently associated with auto-immune diseases, in particular Lupus erythematosus (Farkas et al., 2001, Am. J. Pathol. 159(1)237-43).
Type I interferons (IFN-α, β or ω) are central players in host resistance to viral or microbial infections (Pfeffer et al., 1998, Cancer Res 58(12):2489-99; van den Broek et al., 1995, Immunol Rev 69(8):4792-6). The critical role of pDC in viral infection has been recently demonstrated in vivo, in MCMV and VSV infection models (Dalod et al., 2002, J Exp Med 195(4):517-28; Barchet et al., 2002, J Exp Med 195(4):507-16). Indeed, in the absence of mouse pDC, the level of IFNα is dramatically decreased in mice infected with MCMV. In that study, the anti-Gr1 treatment used to deplete pDC, could in addition to neutrophils, also possibly deplete a proportion of macrophages and of activated T cells. However, because all these cells do not produce IFN-α in vitro and T or B lymphocytes are not required for in vivo production of IFN-α, these data demonstrated that either the MIPC are the only cells able to produce in vivo type I IFN in response to MCMV infection or that their early production of type I IFN is necessary to initiate the cascade of IFN production from other cell types (Dalod et al., 2002, J Exp Med 195(4): p. 517-28).
In humans, resting pDC have been shown to specifically express BDCA-2 and BDCA-4 (Dzionek, et al., 2000, J. Immunol. 165(11):6037-46). In mouse, no such specific markers have been identified to date. It would be of great benefit to identify new markers specific for mouse pDC, in order to monitor, characterize and isolate pDC and also to study their function in vivo in animal models.